Nanoelectronic devices offer substantial potential for interrogating biological systems, although nearly all work has focused on planar device designs. We have overcome this limitation through synthetic integration of a nanoscale field effect transistor (nanoFET) device at the tip of an acute-angle kinked silicon nanowire, where nanoscale connections are made by the arms of the kinked nanostructure and remote multilayer interconnects allow three-dimensional (3D) probe presentation. The acute-angle probe geometry was designed and synthesized by controlling cis versus trans crystal conformations between adjacent kinks, and the nanoFET was localized through modulation doping. 3D nanoFET probes exhibited conductance and sensitivity in aqueous solution independent of large mechanical deflections, and demonstrated high pH sensitivity. Additionally, 3D nanoprobes modified with phospholipid bilayers can enter single cells to allow robust recording of intracellular potentials.
The ability to make electrical measurements inside cells has led to many important advances in electrophysiology1-6. The patch clamp technique, in which a glass micropipette filled with electrolyte is inserted into a cell, offers both high signal-to-noise ratio and temporal resolution1,2. Ideally the micropipette should be as small as possible to increase the spatial resolution and reduce the invasiveness of the measurement, but the overall performance of the technique depends on the impedance of the interface between the micropipette and the cell interior1,2, which limits how small the micropipette can be. Techniques that involve inserting metal or carbon microelectrodes into cells are subject to similar constraints4,7-9. Field-effect transistors (FETs) can also record electric potentials inside cells10, and since their performance does not depend on impedance11,12, they can be made much smaller than micropipettes and microelectrodes. Moreover, FET arrays are better suited for multiplexed measurements. Previously we have demonstrated FET-based intracellular recording with kinked nanowire structures10, but the kink configuration and device design places limits on the probe size and the potential for multiplexing. Here we report a new approach where a SiO2 nanotube is synthetically integrated on top of a nanoscale FET. After penetrating the cell membrane, the SiO2 nanotube brings the cell cytosol into contact with the FET and enables the recording of intracellular transmembrane potential. Simulations show that the bandwidth of this branched intracellular nanotube FET (BIT-FET) is high enough for it to record fast action potentials even when the nanotube diameter is decreased to 3 nm, a length scale which is well below that accessible with other methods1,2,4. Studies of cardiomyocyte cells demonstrate that when brought close, the nanotubes of phospholipid-modified BIT-FETs spontaneously penetrate the cell membrane to yield stable, full-amplitude intracellular action potential recording, showing that a stable tight seal forms between the nanotube and cell membrane. We also show that multiple BIT-FETs can record multiplexed intracellular signals from both single cells and networks of cells.
Nanowire field-effect transistors (NW-FETs) have been shown to be powerful building blocks for nanoscale bioelectronic interfaces with cells and tissue due to their excellent sensitivity and their capability to form strongly coupled interfaces with cell membranes. Graphene has also been shown to be an attractive building block for nanoscale electronic devices, although little is known about its interfaces with cells and tissue. Here we report the first studies of graphene field effect transistors (Gra-FETs) as well as combined Gra-and NW-FETs interfaced to electrogenic cells. Gra-FET conductance signals recorded from spontaneously beating embryonic chicken cardiomyocytes yield well-defined extracellular signals with signal-to-noise ratio routinely >4. The conductance signal amplitude was tuned by varying the Gra-FET working region through changes in water gate potential, V wg . Signals recorded from cardiomyocytes for different V wg result in constant calibrated extracellular voltage, indicating a robust graphene/cell interface. Significantly, variations in V wg across the Dirac point demonstrate the expected signal polarity flip, thus allowing, for the first time, both n-and p-type recording to be achieved from the same Gra-FET simply by offsetting V wg . In addition, comparisons of peak-to-peak recorded signal widths made as a function of Gra-FET device sizes and versus NW-FETs allowed an assessment of relative resolution in extracellular recording. Specifically, peak-to-peak widths increased with the area of Gra-FET devices, indicating an averaged signal from different points across the outer membrane of the beating cells. One-dimensional silicon NW-FETs incorporated side by side with the two-dimensional Gra-FET devices further highlighted limits in both temporal resolution and multiplexed measurements from the same cell for the different types of devices. The distinct and complementary capabilities of Gra-and NW-FETs could open up unique opportunities in the field of bioelectronics in the future.Bioelectronic interfaces created with nanomaterials represents an exciting and growing field of research that exploits key nanomaterial properties to go well beyond the capabilities of conventional microfabricated electronics. 1-8 For example, several groups have recently reported electrical measurements from cells and tissue interfaced to NW-FETs, with results demonstrating high signal-to-noise recording from cultured neurons, muscle cells, embryonic chicken hearts and acute brain slices. [4][5][6][7][8] Unique features of these studies compared to conventional planar devices measurements, include (i) the exceptional small active area of the NW-FET devices and (ii) the fact that nanodevices protrude from the plane of the substrate. The former feature enables high spatial resolution, while the latter can increase device/cell interfacial coupling. Indeed, studies have shown that nanostructured interfaces can enhance cellular adhesion and activity, 9-14 and thus it is likely that NWs and other nanomaterials may...
cardiomyocyte ͉ multiplexed recording ͉ nanodevice ͉ PDMS ͉ silicon
We show that nanowire field-effect transistor (NWFET) arrays fabricated on both planar and flexible polymeric substrates can be reproducibly interfaced with spontaneously-beating embryonic chicken hearts in both planar and bent conformations. Simultaneous recordings from glass microelectrode and NWFET devices show that NWFET conductance variations are synchronized with the beating heart. The conductance change associated with beating can be tuned substantially by device sensitivity, although the voltage-calibrated signals, 4-6 mV, are relatively constant and typically larger than signals recorded by microelectrode arrays. Multiplexed recording from NWFET arrays yielded signal propagation times across the myocardium with high spatial resolution. The transparent and flexible NWFET chips also enable simultaneous electrical recording and optical registration of devices to heart surfaces in three-dimensional conformations not possible with planar microdevices. The capability of simultaneous optical imaging and electrical recording also could be used to register devices to a specific region of the myocardium at the cellular level, and more generally, NWFET arrays fabricated on increasingly flexible plastic and/or biopolymer substrates have the potential to become unique tools for electrical recording from other tissue/organ samples or as powerful implants.Recording electrical signals in vitro and in vivo from whole hearts represents a general methodology useful in areas ranging from basic studies of cardiac function to patient healthcare. 1-6 Low-resolution measurements of activation across the entire heart with, for example macroscale metallic electrodes in contact with the epicardium 2 or optical microscopy of dyed tissue, 3,4 have been used as a diagnostic tool to examine the origins of arrhythmia. 1-4 More recently, higher-resolution recording from embryonic hearts has been achieved using microelectrode arrays (MEAs) with typical electrode diameters and spacings of order 10 and 100 µm, respectively. MEAs can yield more detailed information than larger scale electrodes, for example, on conduction velocities in heart tissue, 4-6 yet a reduction in signal to noise with decreasing MEA electrode size 7,8 will make microns to submicron resolution measurements needed for cellular or subcellular resolution difficult to achieve. Moreover, higher-resolution MEAs have been restricted to planar structures that cannot conform to organs, such as the heart, which are intrinsically three-dimensional (3D) soft objects.An alternative method for electrical recording from biological systems uses NW and carbon nanotube FETs as key device elements. 9,10 These nanoscale FETs have demonstrated higher sensitivity than planar devices for recording local potential changes associated with binding and unbinding of proteins, nucleic acids and viruses 11-14 as well as the propagation of action transparent polymer substrates, 20-22 and thus device chips could be bent to conform to 3D curved surfaces of a heart versus the case of rigid, p...
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